220 urinary cytopathology - its role in diagnostic...

220 Urinary Cytopathology - Its Role in Diagnostic Uropathology and Relationship to Ancillary Tests like FISH

William Murphy MD

2011 Annual Meeting – Las Vegas, NV

AMERICAN SOCIETY FOR CLINICAL PATHOLOGY 33 W. Monroe, Ste. 1600

Chicago, IL 60603

220 Urinary Cytopathology - Its Role in Diagnostic Uropathology and Relationship to Ancillary Tests like FISH Urinary cytopathology is a staple of the systematic evaluation of patients for urothelial neoplasms in nearly all practices and yet it remains problematical to pathologists and clinicians alike. This session will cover specimen handling, diagnostic terminology, histo-cytologic correlations, treatment effects, the cytology of urinary diversions, and ancillary testing, especially FISH. It will be presented in lecture format with ample opportunities for audience participation. Histologic schemes that classify benign lesions as carcinomas, the expectation that all lesions called carcinoma should be recognized in urinary specimens if only the cytopathologists or the methodology were better, and the tendency of pathologists to use temporizing diagnostic terms such as "atypical" and "suspicious" have all contributed to the ongoing frustration with urinary cytopathology and added to the appeal of ancillary tests such as FISH. This presentation is aimed at increasing the confidence of practitioners by identifying the misconceptions and discussing exactly what can be accomplished using urinary cytopathology. For example, the often-emphasized failure of urinary cytopathology to recognize low-grade urothelial neoplasms is an advantage in clinical practice, since these lesions are not life-threatening, can be easily seen endoscopically, and do not require expensive evaluation aimed at early detection and treatment. In contrast, urinary cytopathology is the only method that can separate high-grade, life-threatening urothelial cancers from the low-grade lesions previously mentioned.

• Appreciate the historical roots of histologic classifications of urothelial neoplasms and understand that the definition of malignancy itself has never depended on the characteristics of the component cells.

• Adopt a system, including specific criteria, for the interpretation of urinary specimens that includes specimen handling, diagnostic terminology, and an approach to specimen evaluation and reporting that addresses the concerns of clinicians.

• Understand the role of ancillary testing, especially FISH, in the recognition of neoplastic urothelial cells. FACULTY: William Murphy MD Practicing Pathologists Cytopathology Cytopathology (Non-Gynecologic) 2.0 CME/CMLE Credits Accreditation Statement: The American Society for Clinical Pathology (ASCP) is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education (CME) for physicians. This activity has been planned and implemented in accordance with the Essential Areas and Policies of the Accreditation Council for Continuing Medical Education (ACCME). Credit Designation: The ASCP designates this enduring material for a maximum of 2 AMA PRA Category 1 Credits™. Physicians should only claim credit commensurate with the extent of their participation in the activity. ASCP continuing education activities are accepted by California, Florida, and many other states for relicensure of clinical laboratory personnel. ASCP designates these activities for the indicated number of Continuing Medical Laboratory Education (CMLE) credit hours. ASCP CMLE credit hours are acceptable to meet the continuing education requirements for the ASCP Board of Registry Certification Maintenance Program. All ASCP CMLE programs are conducted at intermediate to advanced levels of learning. Continuing medical education (CME) activities offered by ASCP are acceptable for the American Board of Pathology’s Maintenance of Certification Program.

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Urinary CytopathologyWILLIAM M. MURPHY, MD, FASCP

2011 ASCP Annual Meeting2011 ASCP Annual Meeting

IN ACCORDANCE WITH ACCME GUIDELINES, ANY INDIVIDUAL IN A POSITION TO INFLUENCE AND/OR CONTROL THE CONTENT OF THIS ASCP CME ACTIVITY HAS DISCLOSED ALL RELEVANT FINANCIAL RELATIONSHIPS WITHIN THE PAST 12 MONTHS WITH COMMERCIAL INTERESTS THAT PROVIDE PRODUCTS AND/OR SERVICES RELATED TO THE

2011 ASCP Annual Meeting

CONTENT OF THIS CME ACTIVITY. THE INDIVIDUAL BELOW HAS RESPONDED THAT HE HAS NO RELEVANT FINANCIAL RELATIONSHIP WITH COMMERCIAL INTEREST TO DISCLOSE.

WILLIAM M. MURPHY, MD, FASCP

URINARY CYTOPATHOLOGYHAS BEEN USED CLINICALLY TO ASSESS

NEOPLASMSCRYSTALSBK POLYOMAVIRUSEOSINOPHILS


MICROORGANISMSPARASITES HORMONE STATUSTRANSPLANT REJECTIONHEAVY METALS

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PROBLEMS WITH URINARY CYTOPATHOLOGYIN “BLADDER CANCER”

LOW DIAGNOSTIC YIELD, esp. FOR VOIDED URINE

LOW DIAGNOSTIC YIELD FOR LOW-GRADE TUMORS


LOW COMFORT LEVEL AMONG PATHOLOGISTS

RELATIVELY HIGH INTEROBSERVER VARIABILITY

THE INSISTENCE OF UROLOGISTS ON LABELING ALL UROTHELIAL NEOPLASMS “CANCER”

THE TROUBLE WITHURINARY CYTOPATHOLOGY

INACCURATE HISTOLOGIC CLASSIFICATION


INAPPROPRIATE CLINICAL APPROACH

LACK OF PATHOLOGIST CONFIDENCE

INACCURATE HISTOLOGIC


CLASSIFICATION


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HISTORICAL PATHOLOGYTHE DEFINITION OF MALIGNANCY

THE “INVASION” SCHOOL

PAPILLARY AND NODULAR LESIONSPAPILLOMA


PAPILLOMACARCINOMA

FLAT LESIONSDYSPLASIA - LOW, HIGH GRADEATYPIA - MODERATE, SEVEREDENUDING CYSTITIS

HISTORICAL PATHOLOGYTHE DEFINITION OF MALIGNANCY

THE “RECURRENCE” SCHOOL

PAPILLARY AND NODULAR LESIONSCARCINOMA GRADES 0 4


CARCINOMA - GRADES 0-4FLAT LESIONS

CARCINOMA IN SITUDYSPLASIA, ATYPIA, ???

THE DEFINITION OF MALIGNANCY HAS NEVER DEPENDED ON THE DEGREE OF ANAPLASIA OF THE TUMOR CELLS BUT RATHER THE GROWTH PATTERN OF


RATHER THE GROWTH PATTERN OF THE TUMOR - FOR PAPILLARY UROTHELIAL NEOPLASMS, WE HAVE BEEN TAUGHT TO DIAGNOSE THE STALK, NOT ITS CELLS


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MODERN PATHOLOGYCLASSIFICATION BY CONSENSUS

SCIENCE IS IMPORTANT BUT THE FACTS


ARE IN DISPUTE SO LET’S USE PATHOLOGY ORGANIZATIONS FOR CONSENSUS AND COMPROMISE TO ACHIEVE CURRENT BEST PRACTICE

THE 1973 WHO CLASSIFICATIONOF UROTHELIAL TUMOURS

PAPILLOMACARCINOMA PAPILLARY NODULAR


CARCINOMA - PAPILLARY, NODULARGRADE 1GRADE 2GRADE 3

CARCINOMA IN SITU/DENUDING CYSTITIS


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THE CELLS IN URINARY SPECIMENS HAVE BEEN TELLING US ABOUT THE NATURE OF UROTHELIAL NEOPLASMS FOR 40 YEARS


UROTHELIAL NEOPLASMS FOR 40 YEARS BUT WE WERE NOT PREPARED TO LISTEN


EVIDENCE THAT TCC-1 (1973 WHO) IS NOT A MALIGNANCY

DNA ploidy normal - 95%Chromosome structure normal Almost no abnormalities in genesBlood group antigens retained - 85%


ood g oup a t ge s eta ed 85%Cytology normal 40 - 70%Long-term survival 95% (even with “recurrence”)

Experimental lesions reversibleNeither invasion nor metastasis


TUMOR-SPECIFIC SURVIVAL (YRS)380 CASES WITH AT LEAST A 10 YEAR F/U

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THE CURRENT CLASSIFICATION OF UROTHELIAL NEOPLASMS (1998 WHO/ISUP, 2004 WHO, 2004 AFIP FASCICLE)

PAPILLOMAPUNLMPCARCINOMA

LOW GRADE


LOW GRADEHIGH GRADE

CISDYSPLASIAATYPIA

INAPPROPRIATE CLINICAL APPROACH


(MOST) CLINICIANS REALLY KNOW BETTER


TWO PATIENTS WITH UROTHELIAL TUMORS


UROLOGISTS TELL BOTH THAT THEY HAVE BLADDER CANCER

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URINARY SPECIMENS FROM BOTH PATIENTS


BASICALLY, THERE ARE ONLYTWO GRADES OF UROTHELIAL

NEOPLASMS

LOW GRADE NOT AGGRESSIVE


LOW-GRADE - NOT AGGRESSIVENOT EASILY DIAGNOSED CYTOLOGICALLY

HIGH-GRADE - AGGRESSIVEEASILY DETECTED WHEN CELLS PRESENT


THE PRIMARY CLINICAL VALUE OF URINARY CYTOPATHOLOGY IS THE IDENTIFICATION OF HIGH-GRADECARCINOMA CELLS - UROTHELIAL,


GLANDULAR, SQUAMOUS, SMALL CELL

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SPECIMEN COLLECTIONRANDOM VOIDED

BLADDER WASHING


CATHETERIZED

24 HOUR

EARLY MORNING

VOIDED URINE AND BLADDER WASHING – SAME PATIENT

VU BW


SPECIMEN PRESERVATION

REFRIGERATION

ALCOHOL (25%)


CARBOWAX

RECONSTITUTION IN SALINE

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3 D 5 D


SPECIMEN PROCESSINGCYTOCENTRIFUGATION

THIN PREP/NU VIEW


MEMBRANE FILTERS

DIRECT SMEARS

CLINICAL INFORMATION HELPFULFOR CYTOPATHOLOGIC CONSULTATION

Hx “BLADDER CANCER”(AND GRADE)

HEMATURIA


SPECIMEN SOURCEBLADDER INTESTINAL CONDUITNEOBLADDERBLIND URETHRAURETER, RENAL PELVIS

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DIAGNOSTIC TERMINOLOGY FOR URINARY SPECIMENS

POSITIVE, HIGH GRADE NEOPLASM

SUSPICIOUS - R/O HIGH-GRADE NEOPLASM

DYSPLASTIC CELLS R/O LOW-GRADE NEOPLASM


DYSPLASTIC CELLS, R/O LOW GRADE NEOPLASM

NEGATIVE FOR MALIGNANCY (INCLUDES REACTIVE)NUMEROUS CELLS (ITSELF ABNORMAL)SCANT CELLS

INSUFFICIENT CELLS FOR ANALYSIS

INSUFFICIENT FOR ANALYSIS


WORKING DEFINITION OF ADEQUACYFOR URINARY SPECIMENS

VOIDED URINE OR BLADDER WASHING, NO HISTORY OF “BLADDER CANCER”

AT LEAST 5 NON-SUPERFICIAL CELLS


VOIDED URINE, HISTORY OF “BLADDER CANCER”AT LEAST 5 NON-SUPERFICIAL CELLS

BLADDER WASHING, HISTORY OF “BLADDER CANCER”AT LEAST 15 NON-SUPERFICIAL CELLS

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NORMAL


10xTOO MANY CELLS


40x

CELLULAR FEATURES OF HIGH GRADE UROTHELIAL NEOPLASMS

INCREASED N:C RATIOS (>1:2)INCREASED NUCLEAR SIZE


NUCLEAR ECCENTRICITYNUCLEAR PLEOMORPHISMIRREGULAR, COARSE CHROMATIN

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HIGH-GRADE NEOPLASM UROTHELIAL CARCINOMA, HIGH-GRADE


MTC IN BLADDER WASHING


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HIGH-GRADE NEOPLASM UROTHELIAL CARCINOMA, HIGH-GRADE


10x 40x

COMMON CONFOUNDING FACTORSFOR HIGH-GRADE NEOPLASMS

SCANT CELLS IN VOIDED URINES


TUMOR CELLS THAT LOOK BENIGN

REACTIVE CELLS THAT LOOK MALIGNANT

SCANT MALIGNANT CELLSIN URINARY SPECIMEN


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10x 40x

TYPICAL MTC AFTER BCG


CARCINOMA IN SITU UNDERMINING NORMAL UROTHELIUM


REACTIVE SUPERFICIAL CELL


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REACTIVE CELLS – YOUNG PATIENT WITH BMT


REACTIVE – 33 YO F WITH Tx


TYPICAL (TEXTBOOK) BK CELLS


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BK CELLS IN DAILY PRACTICE


POLYOMAVIRUSES IN URINE ARE (ALMOST) ALWAYS BK.

BK IS UBIQUITOUS IN HUMANS BUT ONLY PATHOGENIC IN PEOPLE WHO ARE IMMUNOCOMPROMIZED.

NUCLEAR INCLUSIONS ARE COMMON AND ARE ESSENTIALLY CONFINED TO SUPERFICIAL CELLS.

BK NUCLEI TEND TO HAVE EVEN CONTOURS AND SMUDGED CHROMATIN; THEY ARE OFTEN DEGENERATED.


WHEN BK CAUSES DISEASE, THE DISEASE IS ALMOST ALWAYS INTHE KIDNEY, NOT THE BLADDER.

IMMUNOCYTOCHEMISTRY IS AVAILABLE BUT NOT NECESSARY IN

MOST CASES; IT IS OFTEN EQUIVOCAL IN PRACTICE

I REPORT BK IN “HEMATURIA” CASES ONLY WHEN THE PATIENT IS IMMUNOCOMPROMIZED OR THERE ARE RED CELL CASTS.

CELLULAR FEATURES OF LOW GRADE UROTHELIAL NEOPLASMS AND DYSPLASIA

INCREASED N:C (>1:2)INCREASED NUCLEAR SIZEEXTREME ECCENTRICITYNUCLEAR BORDER IRREGULARITIES


NUCLEAR BORDER IRREGULARITIESEVENLY DISPERSED, FINE CHROMATINHOMOGENEOUS CYTOPLASM

NB: ALL FEATURES RARELY PRESENT IN EVERY CELL

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CELLS FROM A LOW-GRADE CARCINOMA

DYSPLASTIC CELLS,R/O LOW-GRADE NEOPLASM

UROTHELIAL CARCINOMA, LOW-GRADE


10x 40x

DYSPLASTIC CELLS, R/O LOW-GRADE NEOPLASM LOW-GRADE CARCINOMA


LOW-GRADE CARCINOMADYSPLASTIC CELLS, R/O LOW-GRADE NEOPLASM


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LOW-GRADE CARCINOMA

DYSPLASTIC CELLS, R/O LOW-GRADE NEOPLASM


PUNLMP

4xDYSPLASTIC CELLS, R/O LOW-GRADE NEOPLASM


10x

PUNLMP

4x

DYSPLASTIC CELLS, R/O LOW-GRADE NEOPLASM


20x

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CYTO - HISTOLOGIC CORRELATIONS UROTHELIAL NEOPLASMS

NEGATIVE PAPILLOMAPUNLMP

DYSPLASTIC PUNLMPCa LOW


Ca, LOW GRADESUSPICIOUS Ca, HIGH GRADE

CISPOSITIVE Ca, HIGH GRADE

CISOTHER

COMMON CONFOUNDING FACTORSFOR LOW-GRADE NEOPLASMS

PAPILLARY AGGREGATES


CAUTERY ARTIFACT

NEOPLASTIC CELLS THAT LOOK NORMAL

STONE

57 YO FPELVIC PAIN 24 YO PREGNANT

XRT EFFECT


PELVIC PAIN

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REACTIVE PAPILLARY AGGREGATE


LOW-GRADE NEOPLASM AFTER ELECTROCAUTERY


“NORMAL” CELLS PUNLMP


10x 40x

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AS A PRACTICAL MATTER, NEARLY ALL PATIENTS DYING OF BLADDER CANCER SUCCUMB TO A HIGH-GRADE TUMOR THAT WAS PRESENT AT INITIAL DIAGNOSIS. LESS THAN 10% OF PATIENTS WHO PRESENT WITH A PAPILLOMA OR PUNLMP SUFFER PROGRESSION AND LESS THAN 5% DIE OF BLADDER CANCER (NOBODY DIES OF A PUNLMP).


WHAT THEN IS THE BENEFIT TO PATIENTS OF EARLY DETECTION OF RECURRENT LOW-GRADE TUMORS?

THE PRIMARY CLINICAL VALUE OF URINARY CYTOPATHOLOGY IS TO IDENTIFY PATIENTS WHO NEED MORE AND/OR MORE AGGRESSIVE EVALUATION, USUALLY


CYSTOSCOPY WITH OR WITHOUT BIOPSY. VIRTUALLY NO ONE IS TREATED BASED SOLELY ON A CYTOPATHOLOGIC ASSESSMENT OF A URINARY SPECIMEN.

CLINICAL RESPONSE TO CYTOPATHOLOGICAL DIAGNOSIS

Negative*Dysplastic cells

r/o lg neoplasm

NoneCystoscopy

w/wo biopsy

U/BW RESPONSE


/o g eop asSuspicious

r/o hg neoplasm Positive

hg neoplasm

/ o b opsyCystoscopy

w/wo biopsy Cystoscopy

w biopsy

*scant or numerous cells - check patient status

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CYTOPATHOLOGY CANNOTRELIABLY DISTINGUISH ADENO FROM UROTHELIAL CARCINOMA

DIFFERENTIATE IN SITU FROM


INVASIVE CARCINOMA

LOCALIZE THE LESIONS


UROTHELIAL CARCINOMA, HIGH-GRADE


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ADENOCARCINOMA



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CARCINOMA IN SITU


SQUAMOUS CELL CARCINOMA


SQUAMOUS CELL CARCINOMA


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SMALL CELL CARCINOMA


PCa IN URINE


10x 40x

URINARY CYTOPATHOLOGY IN DAILY PRACTICE


EVEN BELIEVERS HAVE PROBLEMS WITHURINARY CYTOPATHOLOGY

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THE AUA DEFINITION OF “HIGH-RISK” FOR “BLADDER CANCER”

HISTORY OF SMOKINGOLDER THAN 40 YEARSOCCUPATIONAL EXPOSUREGROSS HEMATURIAHISTORY OF IRRITATIVE VOIDING


HISTORY OF IRRITATIVE VOIDINGHISTORY OF UTIsANALGESIC ABUSEHISTORY OF PELVIC XRTHISTORY OF UROLOGIC DISORDER

USING THIS DEFINITION, NEARLY EVERYONE WITHHEMATURIA QUALIFIES FOR ANCILLARY TESTING

DIAGNOSTIC YIELD OF URINARY CYTOLOGY SPECIMENS (%)

A

B

Sens Spec PPV NPV72

72

82

78

92

80

51

69


B

C

D

72

67

60

78

77

87

80

92

95

69

34

32A -D Different scenarios MALIK, UROLOGY, 1999

DIAGNOSTIC YIELD OF UC-MULTIGROUP COLLABORATION (%)

Group A

Group B

Sens Spec PPV NPV47

85

98

74

81

56

91

93


Group B

Group C

Overall

85

66

64

74

98

95

56

88

75

93

94

92A = Academe, B= PP, C= Cancer Center

BASTACKY, CANCER(CANCER CYTOPATHOL), 1999

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URINARY CYTOPATHOLOGY MUST BE CONSIDERED IN TWO MODES – PATIENTS MONITORED FOR “BLADDER CANCER” ARE IN A DIAGNOSTIC MODE;


ARE IN A DIAGNOSTIC MODE;PATIENTS WITH HEMATURIA ARE IN A SCREENING MODE.

THE PPV IS VERY DIFFERENT


TRIUMPHS


TRIUMPHS

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TREATMENT EFFECTS IN URINARY SPECIMENS

ALKYLATING AGENTS – MMC/TTPMALIGNANT-LOOKING SUPERFICIAL CELLS

X-RAYS


NONE

BCGNONE

NECROSIS DUE TO MMC

2011 ASCP Annual MeetingCOURTESY MS SOLOWAY, MD

NORMAL-LOOKING CYSTOSCOPY AFTER MMC


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MITOMYCIN EFFECT


HIGH-GRADE MTC


CIS (LOWER LAYERS) AND MMC EFFECT (SUPERFICIAL CELL LAYER)


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GROSSLY NORMAL BLADDER

2011 ASCP Annual Meeting COURTESY MS SOLOWAY, MD

HIGH-GRADE NEOPLASM


CARCINOMA IN SITU


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CYSTOSCOPY AFTER BCG


HIGH-GRADE NEOPLASM


DENUDATION OF UROTHELIUM, L.P. INVASION


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URINARY CYTOPATHOLOGYAFTER CYSTECTOMY


ILEAL CONDUITSURETHRAL WASHINGS

ILEAL CONDUIT URINE


ILEAL CELLS


MTC

MTC

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HIGH-GRADE CARCINOMA RENAL PELVIS


URETHRAL STUMP WASHING


10x 40x

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CIS IN PARAURETHRAL GLANDS



URETHRAL STUMP WASHING


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CIS IN PARAURETHRAL GLANDS



WHAT ABOUT CELLS FROM THE UPPER COLLECTING SYSTEM?

LOW-GRADE NEOPLASMS DON’T LEND THEMSELVES TO CYTOPATHOLOGIC DIAGNOSIS

IT IS NOT UNCOMMON TO SEE HIGH-GRADE CELLS IN SPECIMENS FROM BOTH SIDES EVEN THOUGH THE TUMOR


SEEMS TO BE ON ONLY ONE SIDE

RENAL CELL CARCINOMAS ARE RARE IN UPPER SYSTEM SPECIMENS

ALL TYPES OF EVALUATION MUST CORRELATE BEFORE RESECTION

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NORMAL CELLS IN RENAL PELVIS WASHING


NORMAL CELLS, LEFT MALIGNANT CELLS, RIGHT


URETERAL WASHING

POSITIVE, HIGH-GRADE NEOPLASM

UROTHELIAL CARCINOMA, HIGH-GRADE 4x


40x

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ESTABLISHED METHODS TO DETECTUROTHELIAL NEOPLASMS

HEMATURIA (w OR w/o IRRITATIVE VOIDING Sx)


CYSTOSCOPY (w OR w/o BIOPSY)

URINARY CYTOPATHOLOGY

TYPICAL CASE – NBCCG-ADATE CYSTO CYTO HISTO

5/75 POS ND TCC-II, CIS7/75 POS S DYS10/75 S POS CIS2/76 POS POS TCC-II, CIS4/76 S NEG DENUDED7/76 NEG NEG NEG11/76 NEG DYS DYS3/77 NEG DYS NEG


3/77 NEG DYS NEG9/77 NEG S --12/77 S POS NEG2/78 NEG POS --3/78 S S --7/78 S POS TCC-II, CIS11/78 NEG POS --2/79 NEG POS --6/79 NEG NEG --9/79 POS -- TCC-II, CIS1/80 NEG S --4/80 POS NEG TCC-III6/80 POS POS TCC-III

OK, SO WE NOW KNOW THE LIMITATIONS AND CLINICAL USES OF URINARY CYTOPATHOLOGY.


CAN’T WE DO BETTER WITH ANCILLARY METHODS?

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ANCILLARY TESTS FOR BLADDER NEOPLASMS

TISSUE PRODUCTS - BTA, NMP22, DD23BLOOD GROUP ANTIGENS - ABH, LEWIS XCYTOKERATINS - CK20, CYFRA 21-1, TPA, UBCPROTEINS/MUCINS - IMMUNOCYT, URO IIENZYMES - TELOMERASE, HA/HAase


,GROWTH FACTORS - EGF, TGFADHESION MOLECULES - CD44, E-cadDNA - QUANTICYTCHROMOSOMES - UROVYSION FISH, MSGENES

PROBLEMS WITH THE CLINICAL APPLICATION OF MARKERS

VERY FEW MARKERS SPECIFIC (ONLY PSA, URO)MANY REACT VARIABLY EVEN IN TYPICAL CASESNO MARKER IS DIAGNOSTIC FOR MALIGNANT UROTHELIAL CELLS

IF USED FOR DETECTION, LOW PPV LIMITS VALUE EVEN IF HIGH SENSITIVITY AND SPECIFICITY

IF USED FOR DDx, FOCAL REACTIONS OFTEN LEAD TO HIGH


,INTEROBSERVER VARIATION; IMAGING, HISTORY BETTER

IF USED FOR PROGNOSIS, OVERLAP BETWEEN GROUPS OFTEN TOO LARGE FOR PATIENT CARE; HYPOCELLULARITY LIMITS USE

WITH FEW EXCEPTIONS, IMMUNOCYTOCHEMISTRY HAS BEEN DIFFICULT TO APPLY IN MOST PRACTICES

IF MANY ABNORMAL CELLS, IS IT NECESSARYIF FEW ABNORMAL CELLS, IS IT RELIABLE

DO YOU NEED IMMUNOS TO DIAGNOSE THIS?


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WOULD YOU BELIEVE THE IMMUNOS IN THIS CASEOR WOULD YOU CALL IT SUSPICIOUS ANYWAY?


THE SEARCH FOR BETTER METHODS TO DETECT UROTHELIAL NEOPLASMS IS NOT NEW - WHAT’S NEW IS THE COMMERCIAL


NEW WHAT S NEW IS THE COMMERCIAL AVAILABILITY OF URINE-BASED MARKERS AND FDA APPROVAL (THE ABILITY TO GAIN FINANCIALLY FROM THE TESTS)

JUSTIFICATION FOR FISHEMPIRICAL OBSERVATIONS REVEALABERRATIONS IN CHROMOSOMES

3 RED7 GREEN17 AQUA9 YELLOW


9 YELLOWCOINCIDE WITH THE PRESENCE OF UROTHELIAL NEOPLASMS

DIAGNOSTIC YIELD IS 15-50% BETTERTHAN VOIDED URINARY CYTOLOGY

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510k CLINICAL DATAUroVysion Bladder Cancer Recurrence Kit

TM

SENSITIVITY (%) BY GRADE

GRADE n FISH BTAstat CYTOLOGY


2

1

3

22

9

18

55

78

94

27

78

72

18

44

41

SOURCE: 2001 AUA Poster 664, Sarosdy et al.

DIAGNOSTIC ACCURACY OF URINARY CYTOLOGY -HIGH GRADE CARCINOMA*

Voutsa

Schoonees

De Voogt

Esposti

Year Patients % Pos

1963

1971

1972

1972

20

102

20

274

100

82

85

71

Author+


Loening

Rife

1978

1979

79222

536 72

Friedell

Murphy

Shenoy

1982

1984

1985

183

43

26

62

100

100 +

*weighted average of grades II & III TCC and CIS +only CIS evaluated

SO YOU WANT TO FISHFOR BLADDER CANCER

EQUIPMENT ($90,000 plus)

SUPPLIES (>$125/TEST)

LOGISTICS (PREPARATION, TRANSPORT)


PERSONNEL (TECH LICENSED FOR HIGHCOMPLEXITY)

SPACE (FOR DARK FIELD MICROSCOPE)

RECORD MAINTENANCE (COMPUTER, CAMERA)

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ESTIMATING INCOME FROM FISH1 2

SPECS/YR 2000 2000% BlCa F/U 25 N/A% HEMATURIA N/A 100 # ELIGIBLE FOR FISH 500 2000 LESS 20%(FEW CELLS, ETC) 400 1600 LESS 10%(POS CYTO) 360 N/A


LESS 10%(POS CYTO) 360 N/ALESS 2% (POS CYTO) N/A 1568

INCOME (@ $200/SPEC) $72,000 $313,600SCENARIO 1: ONLY BLCA F/U; SCENARIO 2: ALL HIGH-RISK HEMATURIA

DEFINITION OF POSITIVE FISHAT LEAST 25 EPITHELIAL NUCLEI ON THE SLIDE

AT LEAST 4 NUCLEI WITH:>2 SIGNALS OF 3&7,3&17, 7&17

OR>11 NUCLEI LACKING 9


>11 NUCLEI LACKING 9

(SOME ALSO INCLUDE TRISOMY 3,7, OR 17IN AT LEAST 10% OF NUCLEI)

IN PRACTICE, MOST ABNORMALS ARE IN 3&7ABNORMAL 9 IS UNUSUAL (<10%)ALL NUCLEI MUST BE ASSESSED


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PROBLEMS WITH FISH ANALYSIS

SPECIMENS WITH 1-3 ABNORMAL NUCLEI WEAK/ABSENT YELLOW SIGNALS NON-SPECIFIC SIGNALS, ESP. REDWIDELY SPLIT SIGNALSTETRAPLOID SUPERFICIAL CELLS


TETRAPLOID SUPERFICIAL CELLS>2 RED/GREEN, RETENTION OF YELLOWAUTOFLUORESCENCE NUCLEAR CLUMPINGNEUTROPHILSPPV BlCa 50%, PPV HEM 3% - 24%

FISH (NOV 05 - JUNE 08)

TOTAL SPECIMENS FISH NOT DONE

POOR PRESERVATION POSITIVE CYTOLOGY

FISH PERFORMED

1278

268 (21%)78 (6%)932


FISH PERFORMED UNINFORMATIVE NEGATIVE POSITIVEABNORMAL (2,3 CELLS)

93248 (5%)768 (82%)57 (6%)60 (7%)

CASES WITH POSITIVE FISH35 PATIENTS; 57 SPECIMENS

TUMOR AT FOLLOWUP (1-32m)CYTOLOGY SUSP/DYS/POSCYTOLOGY NEGATIVE CYTOLOGY NOT DONE

11533


NO TUMOR AT FOLLOWUP (1-32m)

NO FOLLOWUP

24

0

DIAGNOSTIC YIELD = 31% (of 6% = 1.8%)

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CASES WITH ABNORMAL FISH46 PATIENTS; 60 SPECIMENS

TUMOR AT FOLLOW-UPCYTOLOGY SUSP/DYS/POSCYTOLOGY NEGATIVECYTOLOGY NOT DONE

13562


NO TUMOR AT FOLLOW-UP

NO FOLLOW-UP 4

29

2

DIAGNOSTIC YIELD = 28% (of 7% = 2%)

THE PRIMARY JUSTIFICATION FOR FISH IS ITS HIGH SENSITIVITY, USUALLY COMPARED TO VOIDED URINARYCYTOPATHOLOGY.

THIS SENSITIVITY IS ACQUIRED AT THE COST OF POSITIVE PREDICTIVE VALUE (ABOUT 50% FOR PATIENTS BEINGFOLLOWED FOR “BLADDER CANCER” AND 3-25% FOR PEOPLE WITH HEMATURIA). THE PPV CAN BE INCREASEDWITH MULTIPLE TESTS AND WHEN CYTOPATHOLOGY IS ABNORMAL BUT SO CAN THE RESULTS OF CYTOPATHOLOGY.


FISH CANNOT DISTINGUISH AGGRESSIVE FROM INDOLENT NEOPLASMS AND UROLOGISTS ARE VERY UNLIKELY TO TREAT SOLELY ON THE BASIS OF FISH.

PATIENTS BENEFIT PRIMARILY FROM CHANGES IN THEFREQUENCY AND/OR AGGRESSIVENESS OF THEIR EVALUATIONS.

SO, WHAT CHANGES IN EVALUATION OR FOLLOWUP ARE LIKELY WHEN A PATIENT HAS A POSITIVE TEST THAT IS LIKELY TO BE CORRECT ONLY 3-25% (HEMATURIA) OR 50% (MONITORING) OF THE TIME?

PATIENTS WITH HEMATURIA AND A POSITIVE FISH COULD BE EVALUATED (?AGGRESSIVELY) FOR A UROTHELIAL NEOPLASM. HOW OFTEN IF NO LESION IS FOUND HAS NOT BEEN ADDRESSED?

PATIENTS WITH HEMATURIA AND A NEGATIVE FISH COULD AVOID A BLADDER TUMOR EVALUATION.

FOR PATIENTS WITH UROTHELIAL NEOPLASMS, LESS FREQUENT FOLLOWUP MIGHT


BE JUSTIFIED IF THE INITIAL TUMOR WERE LOW-RISK (PUNLMP/LOW-GRADE,Ta)

CYSTOSCOPY AT EACH VISIT COULD DEPEND ON FISH REMAINING NEGATIVE.

MORE FREQUENT AND AGGRESSIVE FOLLOWUP SOLELY FOR A POSITIVE FISH WOULD BE HARD TO JUSTIFY CONSIDERING THE LOW PPV AND THE INABILITY OF THE TEST TO IDENTIFY HIGH-RISK LESIONS.

LESS FREQUENT MONITORING WOULD BE HARD TO JUSTIFY FOR ANY PATIENT WITH A HIGH-RISK NEOPLASM.

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FISH FACTORSSAME AS UC - LONG LEAD TIME, FLUCTUATING RESULTS, DIFFICULT TO INTERPRET RESULTING IN HIGH INTEROBSERVER VARIABILITY, HIGH COMPLEXITY TECHNOLOGISTS REQUIRED

DIFFERENT FROM UC - HIGHER SENSITIVITY, SPECIFICITY BUT LESS RELIABLE RESULTS (LOWER PPV), HIGHER COSTS AND REIMBURSEMENT


REIMBURSEMENT

•IF PATIENTS PRESCREENED WITH CYSTO, FISH SHOULD BE COMPARED WITH BW, NOT VU

•COST EFFECTIVENESS VS UC NOT ADDRESSED

•FISH BEST (cf VU) FOR LOW-GRADE, NON-INVASIVE NEOPLASMS BUT NEED FOR EARLY DETECTION QUESTIONABLE

WHO SHOULD GET A FISH?

PATIENTS WHOSE MANAGEMENT WILLBE CHANGED BY THE RESULT


“BlCa” F/U WITH NON-POSITIVE CYTOLOGYABNORMAL CYSTO, NON-POSITIVE CYTOSPECIAL PROTOCOLS OF THE PRACTICE

“BlCa” PATIENT - CYTOLOGY SUSP, CYSTOSCOPY NEG


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WHO SHOULD NOT GET A FISH?

PATIENTS WHO WILL BE FOLLOWED AGGRESSIVELY ANYWAY i.e. THEY HAVE A HIGH-RISK INDEX TUMOR (HIGH-GRADE UCa, CIS, TI-2, NON- UCa)

PATIENTS WITH A POSITIVE CYSTOSCOPY


PATIENTS WITH A POSITIVE CYSTOSCOPY

PATIENTS WITH A POSITIVE CYTOLOGY

PATIENTS WITH VERY LOW-GRADE INDEX LESIONS(PUNLMP, PAPILLOMA, DYSPLASIA)


URINARY CYTOPATHOLOGY IS THE ONLY CURRENTLY AVAILABLE METHOD THATCAN DISTINGUISH AGGRESSIVE UROTHELIAL CARCINOMAS FROM NON-AGGRESSIVE UROTHELIAL NEOPLASMS


UROTHELIAL NEOPLASMS.

IT REMAINS THE BEST WAY TO MONITOR PATIENTS FOR RECURRENT/PERSISTENT DISEASE.

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220 urinary cytopathology - its role in diagnostic...

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